Substituted alpha-cycloalkylidene-alpha-phenyl-cresol ethers

ABSTRACT

SUBSTITUTED A-CYCLOALKYLIDENE-A-PHENYL-CRESOL ETHERS, PROCESSES FOR THE PREPARATION THEREOF AND NOVEL INTERMEDIATES PREPARED BY SAID PROCESSES. THE NOVEL SUBSTITUTED CRESOL ETHERS HAVE UTILITY AS ANTILIPEMIC AGENTS, ANTIFUNGAL AGENTS AND INSECTICIDES.

.7 o 3,658,842 Umted States Patent Olfice ted A r, 25, 19.2

The novel processes for making the novel compounds 3,558,342 of thisinvention are illustrated in the following equations:

SUBSTITUTED a-CYCLOALKYLIDENE- O R a-PHENYL-CRESOL ETHERS H DanielLednicer, Kalamazoo, Mich., assignor to The 5 112) EE -Q Upjohn Company,Kalamazoo, Mich. No Drawing. Filed Feb. 11, 1969, Ser. No. 798,457

Int. Cl. C07d 27/04, 27/10 11 A US. Cl. 260-326.5 M 7 Claims ABSTRACT OFTHE DISCLOSURE Substituted a-cycloalkylidene-a-phenyl-cresol ethers,processes for the preparation thereof and novel intermediates preparedby said processes. The novel substituted cresol ethers have utility asantilipemic agents, antifungal agents and insecticides. Orr/Q BRIEFSUMMARY OF THE INVENTION \j This invention relates to novel compounds,processes for the preparation of the same and novel intermediatesprepared by said processes. The novel compounds of this l invention havethe formula:

15 MgBr III R IV R I wherein R represents hydrogen, alkyl containingfrom 1 to OR, OCH CHOH 4 carbon atoms, inclusive, alkoxy containing from1 to 4 carbon atoms, inclusive, and halogen; R is alkyl substif tuted bya group selected from the class consisting of (a) (0112) 0:0 (CH2)n\C=O/dihydroxyalkyl having from 2 to 5 carbon atoms, inclusive, (b) the groupIa R V R3 A wherein R and R individually are similar or different alkylgroups containing from 1 to 4 carbon atoms, in- (I311 elusive, and whentaken together with the attached nitro- OCH CH gen atom form the residueof a saturated heterocyclic amine containing from 5 to 7 members,inclusive, in the ring and m is an integer from 1 to 4, (c)5-(2-thioxooxg azolidinyl)-, (d) epoxyethyl, (e) 2,Nsuccinimido-1-hy- 2n T droxyethyl, and (f) 2-amino-1-hydroxyethyl, and n is an integer from2 to 7. VI

The term dihydroxyalkyl having from 2 to 5 carbon atoms, inclusiveincludes 1,2-dihydroxyethyl, 1,3-dihyl CHzN droxypropyl,2,3-dihydroxypropyl, 1,4-dihydroxybutyl and the like. 7

The term saturated heterocyclic amine containing from 5 to 7 members;inclusive, in the ring is inclusive of pyr- OCH2CH'OH2NH2 rolidino,alkylpyrrolidino such as 2-methylpyrrolidino, 2,2-

( H2 o=o dimethylpyrrolidino, 3-methylpyrrolidino and the like;piperazino, alkylpiperazino, such as Z-methylpiperazino,4-methylpiperazino, 2,4-dimethylpiperazino; piperidino, Qalkylpiperidino such as Z-methylpiperidino, 3-methyl- VII R piperidino,4,4-dimethylpiperidino, and the like; morpholino, hexamethylenimino,homopiperazino and the like. l

The term novel compounds of this invention as used throughout thespecification embraces the compounds rep- OGH2CH (JH2 resented by theFormula I above, the acid addition salts Q 0 N of those compoundswherein R contains an amino sub- ((3H,)u 0:0 stituent and quaternaryammonium salts of those com- U \Q g pounds wherein the substituent Rcontains a tertiary amino group. no R The starting cycloalkyl arylketones (II) are readily prepared by reacting an acid having the formulaadmin.

VIII

wherein n is the same as above, and the appropriately substitutedbenzene. The acid is first converted to its corresponding acyl chlorideand then the acyl chloride is allowed to react with the benzene compoundin the presence of a Lewis acid, such as aluminum chloride or borontrifluoride. This represents the classical Friedel-Cratts reaction. Allof the acids embraced by Formula VIII are known and can be prepared byprocedures that are well known in the art.

The compounds of Formula I wherein R is alkyl substituted by adihydroxyalkyl group or a tertiary aminoalkyl group (Ia) are prepared inaccordance with reaction scheme A, B and C.

In reaction A the ketone (II) is reacted with the Grignard reagentobtained from p-(Z-tetrahydropyrariyloxy) bromobenzene. The reactionproceeds smoothly at room temperature (25 C.); however, if desired itmay be conducted at higher or lower temperatures.

Reaction B represents dehydration of the carbinol (III) to form ana-cycloalkylidine-a-phenyl-cresol (IV The dehydration may be carried outby heating the carbinol either alone or in the presence of variousmaterials. For example, it may be heated either under atmospheric pres:sure or under a vacuum in the presence of potassium acid sulfate or itmay be refluxed in benzene in the presence of p-tolunesulfonic acid.Details of this type of dehydration along with various other materialsthat maybe utilized to facilitate it are described in US. Pat. No.3,287,397.

The alkylation of the a-cycloalkylidene-u-phenyl-cresol (IV) to form theethers of Formulae Ia and V (Reactions C and D, respectively) is readilyaccomplished by methods well known in the art for the etherification ofphenols.

Illustratively, the compounds of Formula Ia wherein R;

is tertiaryaminoalkyl can be prepared by treating the compound ofFormula IV with the appropriate tertiaryaminoalkyl halide in thepresence of a base such as sodium hydride, sodium methoxide and thelike. The etherification is conducted advantageously in the presence ofan inert organic solvent such as tetrahydrofuran, dioxane,dimethylformamide or benzene.

Similarly the compounds of Formula Ia wherein R' is alkyl substituted bydihydroxy alkyl and the compound of Formula V, which is substituted byepoxyethyl, can be prepared by alkylating the compounds of Formula IVwith the appropriate dihydroxyalkyl halide (Reaction C) and epoxyalkylhalide (Reaction D) respectively in the presence of a base such assodium hydroxide, sodium methoxide, and the like. The alkylation isconducted advantageously in the presence of an organic solvent such astetrahydrofuran, dioxane, a lower alkanol, e.g., methanol, ethanolisopropanol, and the like.

The compounds of Formula I, wherein R is 5-(2-thioxooxazolidinyl)- areprepared in accordance with reaction scheme A, B, D, E and F. Steps A, Band D have been described above.

In step (E), the epoxy (V) is reacted with succinimide in the presenceof a base such as pyridine, piperidine, N- rnethyl-piperidine, and thelike, whereby the epoxy ring is opened and the correspondingN-3-[[a-cycloalkylidenea-phenyl-tolynoxy]-2-hydroxy-propylsuccinimide(VI) is obtained. The compound of Formula VI is reacted first with amixture of sodium hydroxide and then .with an aqueous solution of ahydrohalide (Step F) to yield the corresponding 3-[a-cycloalkylidene-oephenybtolyl] oxy] 2-hydroxy-propylaminehydrohalide. The hydrohalide is then reacted with a solution ofmethanolic sodium methoxide to yield3-[[a-cycloalkylidene-oc-phenyl-tolyl] oxy]- 2-hydroxypropylarnino(VII).

In the final step (G), the compound of Formula VII is converted to thecorresponding5-[[[a-cycloalkylidenea-phenyltolyfloxy]methyl]-2-oxazolidenethione, byreaction with carbon disulfide in the presence of a base such aspotassium hydroxide, sodium hydroxide, potassium carbonate, and thelike. The procedures employed can be those described in the art; see,for example, Bruson et al., J. Amer. Chem. Soc. 59, 2011, 1937. Thereaction is preferably conducted in the presence of an organic solventsuch as tetrahydrofuran, dioxane, ethanol, isopropyl alcohol, and thelike. Also, elevated temperatures e.g., the reflux temperature of thereaction mixture, are advantageously employed in the reaction.

The acid addition salts of the invention comprise the salts of thecompounds of Formula I wherein R contains an amino substituent withpharmacologically acceptable acid such as sulfuric, hydrochloric,nitric, phosphoric, lactic, benzoic, methanol-sulfonic,p-toluenesulfonic, salicylic, acetic, propionic, maleic, malic,tartaric, citric, cyclohexanesulfamic, succinic, nicotinic, ascorbicacids, and the like.

The quaternary ammonium salts of the invention are the salts obtained byreacting the tertiary amino compounds of Formula -I with quaternatingagents, for example, alkyl halide, alkenyl halides, dialkyl sulfates,alkyl arylsulfonates, and the like. The term alkyl means an alkyl groupcontaining from 1 to 4 carbon atoms, inclusive. The term alkenyl meansan alkenyl group containing from 3 to 8 carbon atoms, inclusive, such asallyl, butenyl, penteuyl, hexenyl, heptenyl, octenyl, and isomeric formsthereof. The term aralkyl means an aralkyl group containing from 7 to 13carbon atoms, inclusive, such as benzyl, phenylethyl, phenylpropyl,benzhydryl and the like. The term alkyl arylsulfonate means the estersformed from alkanols and arylsulfonic acids such as benzenesultonic,toluenesulfonic, xylenesulfonic, and like acids. Examples of quaternarysalts of the compounds of the invention are the methobromide,methiodide, ethobromide, propyl chloride, butyl bromide, octyl bromide,methyl metho sulfate, ethyl ethosulfate, allyl chloride, allyl bromide,benzyl bromide, benzhydryl chloride, methyl toluenesulfonate, ethyltoluenesulfonate, and the like.

The novel compounds of this invention are useful in the treatment ofhyperlipemic states in animals. illustratively, the compounds3-[[a-cyclohexylidene-a-(p-methoxyphenyl) -p-tolyl] oxy]-1,2-propanedioland 1- [2- [acyclohexylidene-a-(p-methoxyphenyl) ptolyl]oxy]ethyll-pyrrolidine hydrochloride when administered orally toSprague-Dawley male rats exhibited serum cholesterol and triglyceridereducing activity.

.Also, the compounds of Formula I, wherein R is alkoxy substituted by atertiaryamino alkyl group, have been found to have antifungal activity.For example, in concentrations of 50 mcg./ml., both thel-[2-[[u-cyclopen tylidene-ot-(p-ethoxyphenyl) ptolyl]oxy]ethyl]pyrrolidine hydrochloride andl-[2-[[a-cyclohexylidene-u- (p-methoxyphenyl) ptolyl]oxy]ethyl]-pyrro1idine hydrochloride inhibit the growth of Pythiumdebaryanum. In addition, the same concentration of the later compoundinhibits the growth of Rhizoctonia solam'. Both of these compounds alsoexhibit insecticidal activity when they are made part of a solution(concentration of about 0.2 percent) and applied to crickets.

The compounds of Formula I wherein R is lower alkyl substituted by5-(2-thioxooxazolidinyD- also exhibit insec ticidal activity whenapplied to crickets in concentrations of about 0.2 percent.

The compounds of Formula I wherein R is lower alkyl substituted bydihydroxyalkyl wherein dihydroxyalkyl is as hereinbefore described, andn is 4, also exhibit anticonvulsant activity when administeredintraperitoneally to mice at a dosage of 30 mg./kg.

For purposes of administration to birds and to mammals, includinganimals of economic value such as horses, cattle, sheep, pigs, mice,rats, rabbits and the like, the novel compounds of the invention can becombined with solid or liquid pharmaceutical carriers and formulated inthe form of tablets, powder packets, capsules, and like solid dosageforms, using starch and like excipients, or dissolved or suspended insuitable solvents or vehicles for oral or parenteral administration.

EXAMPLE 1 a-Cycloh exylidene-u- (p-meth oxyphenyl -pcresl A solution of16.20 g. of cyclohexyl p-methoxyphenyl ketone in 150 ml. oftetrahydrofuran is added to a solution of the 'Grignard reagent preparedfrom 20 g. of p-(tetra hydropyranyloxy)-bromobenzene and 2.0 g. ofmagnesium in 200 ml. of tetrahydrofuran. Following 15 hours standing atroom temperature the mixture is treated with 150 ml. of 2.5 Nhydrochloric acid. The organic layer is separated, washed with water anda saturated solution of sodium chloride and taken to dryness. Theresidue is dissolved in 600 ml. of methanol and 150 ml. of 2.5 Nbydrochloric acid is added. The mixture is stirred at 25 C. for 4 hoursand the bulk of the solvent removed in vacuum. The waxy solid which cameout is collected on a filter and dissolved in ether. The organicsolution is washed with water and a saturated solution of sodiumchloride and taken to dryness. The residue is recrystallized twice fromcyclohexane to give 6.64 g. of solidtat-cyclohexylidene-a-(p-methoxyphenyl)p-cresol melting point 143- 146C. (lit. 145-146 C.).

Using the procedure described in Example 1 but replacingcyclohexyl-p-methoxyphenyl ketone by cyclohexyl phenyl ketone,cyclohexyl-p-methylphenyl ketone, and p-chlorophenyl cyclohexyl ketone,there are obtained (a-cyclohexylidene-u-phenyl)-p-cresol,tat-cyclohexylidenecz-(p-methylphenyl)-p-cresol andoc-(P-ChlOI'OPhCIlYD-acyclohexylidene-p-cresol respectively.

EXAMPLE 2 3-[ [a-cyclohexyliden'e-a- (p methoxyphenyl) -ptolyl]-0xy]-1,2pr0panedi0l A solution of 2.40 g. of a cyclohexylidene a(pmethoxy-phenyl) p cresol (Example 1) in 50 ml. of methanol is treatedwith 2.01 ml. of 4.46 methanolic sodium in methanol. Following 15minutes stirring at a temperature of 25 C. 1.01 g. of1-chloro-2,3-propanediol is added and the mixture heated at reflux for16 hours. Methanol is removed and the residue dissolved in a mixture ofether and Water. The organic layer is separated, washed with water and asaturated solution of sodium chloride and then taken to dryness. Theresidual gum is chromatographed over Florisil (magnesium silicate)(elution with and then 50 percent acetone in Skellysolve B hexanes) togive 1.60 g. of crude product. This product is recrystallized twice fromaqueous methanol to afford 1.58 g. of crystalline 3-[[ct-cyclohexylidenecc (p-methoxyphenyD-p-tolyl]oxy] 1,2 propanediol,melting point 97-99 C.

Analysis.-Calcd. for C H O (percent): C, 74.97; H, 7.66. Found(percent): C, 74.79; H, 7.88.

Using the procedure described in Example 2, 'but replacingtat-cyclohexylidene a (p methoxyphenyl)-pcresol by the appropriatelysubstituted a-cyclohexylidenea-phenyl-cresol is productive of thecorresponding cyclohexylidene a phenyltolyl]oxy]-1,2-propanediol.Representative of the propanediols so obtained are:

3 [a-cyclohexylideneoz- (o-methoxyphenyl -otolyl] oxy] 3[a-cyclohexylideneoc- (m-methoxyphenyl) -mtolyl] oxy] 3-[a-cyclohexylidenea-phenyl-p-tolyl] oxy] 3-[ [a-cyclohexylidene-2-(p-methylphenyl -ptolyl] oxy] 3- [a-cyclohexylidene-ap-chlorophenyl -pty y]-,

3-[ [a-cyclohexylidene-a- (o-chlorophenyl -ptolyl]oxy] 3-[a-cyclohexylidenea- (m-chlorophenyl) -ptolyl] oxy] 3-[[a-cyclohexylidene-u- (p-methoxyphenyl -otolyl] oxy] 3[a-cyclohexylidene-am-methoxyphenyl) -mtolyl] oxy] -1,2-propanediols.

Similarly, using the procedure described in Example 2, but replacing 1chloro 2,3 propanediol with 1- chloro 3,4 butanediol there is obtained4-[[a-cyclohexylidene a (p-methoxy-phenyl) p tolyl]oxy]-1,2- butanediol.

EXAMPLE 3 1 [2 [[a cyclohexylidene oz (p meth0xyphenyl)- ptolyl]oxyJethyl] pyrrolidine and hydrochloride thereof A solution of2.50 g. of acyclohexylidene-u-(p-methoxyphenyl)-p-cresol (Example 1) in20 ml. of dimethylformamide and 100 ml. of benzene is treated with 0.36g. of 56% sodium hydride in mineral oil. When the efi'ervescence hasceased, 2.17 g. of a 1:1 mixture of a B-chloroethylpyrrolidine andtoluene is added. The mixture is heated overnight at reflux and thesolvent remove-d in vacuum. The residue is taken up in a mixture ofether and water and then the ether and aqueous phases are separated. Theether phase is extracted with three portions of 2.5 N hydrochloric acid.This extract is then Washed with five portions of methylene chloride.After the fifth Washing, the mixture is taken to dryness and the residuerecrystallized twice from methanol. There is obtained 3.07 g. of 1 [2[[a cyclohexylidene a (p methoxyphenyl) p tolyl]oxy] ethyl] -pyrrolidinehydrochloride, melting point 97 C.

Analysis.-Calcd. for C H ClNO (percent): C, 72.96; H, 8.01; Cl, 8.26.Found (percent): C, 72.34; H, 8.27; Cl, 8.30.

The free base is prepared by basifying the hydrochloride With methanolicsodium methoxide and evaporating the mixture to dryness.

Using the procedure described in Example 2, but replacingu-CYClOheXYlldEIIC a (p methoxyphenyl)-pcresol by the appropriatelysubstituted wcyclohexylidenea nethoxyphenyl-p-cresol and 13chloroethylpyrrolidine by the appropriately substitutedtertiaryaminoalkylhalide, there are obtained the correspondingsubstituted [[[cyclolrexylidene a phenyl p tolyl]oxy]alkyl]amines andthe hydrochlorides thereof. Representative of the substituted[[[cyclohexyldiene oz phenyl p tolyl] oxy]- alkyl]-arnines andcorresponding hydrochlorides so prepared are 1- [2-[a-cyclohexylidene-u- (o-methoxyphenyl) -otolyl] oxy] ethyl] 1- 2-[m-cyclohexylidene-uo-methoxyphenyl) -mtolyl] oxy] ethyl] 1-2-[u-cyclohexylideneu-phenylp-tolyl] oxy] ethyl] 1- [2-[a-cyclohexylidene-w(p-methylphcnyl) -ptolyl] oxy] ethyl] l- [2- [ucyclohexylidene-a- ('p-chlorophenyl) -ptolyl] oxy] ethyl] 1- {2-[[a-cyclohexylidene-a- (o-chlorophenyl) -ptolyl] oxy] ethyl] 1- 2-[[a-cyclohexylidene-a- (m-chlorophenyl) -ptolyl] oxy] ethyl] 1- [2-[wcyclohexylidene-a- (pqnethoxyphenyD tolyl] oxy] ethyl] 1-[ 2-[[a-CYClOhGXYlidCHC-ot- (m-methoxyphenyl) -mtolyl] oxy] ethyl] 1-2-[[a-cyclohexylidene-a- (m-methoxyphenyl -ptolyl] oxy] ethyl] 1 3[[a-cyclohexylidene-a- (m-methoxyphenyl) -ptolyl] oxy] ethyl] 1 [4-[[u-cyclohexylidene-a- (p methoxyphenyl) -ptolyl] oxy]butyl]-pyrrolidines,

1- [21 [u-cyclohexylideneup methoxyphenyl) -ptolyl]oxy] ethyl] -epiperazine,

1- [2-[ [a-eyclohexylidene-a- (p-methoxyphenyl) -ptolyl] oxy] ethyl]-piperazine,

4- [2- [u-cyclohexylidene-ap-methoxyphenyl) -ptolyl] oxy] ethyl]-morpholine,

1- [2- [a-cyclohexylidene-a- (p-rnethoxyphenyl) ptolyl] oxy] ethyl]-hexamethyleneimine,

1- 2-[ [u-cyclohexylidenecc- (p-methoxyphenyl) -ptolyl] oxy] -etl1yl]-3-methylpyrrolidine,

1- ['2- [a-cyclohexylidene-a- (p-methoxy-phenyl) ptolyl] oxy] ethyl]-4-methylpiperazine,

1- [2-[ [u-cyclohexylidene-a- (p-methoxyphenyl) -ptolyl] oxy] ethyl]-2-methylpiperidine,

2- [a-cyclohexylidene-2- (p-methoxyphenyl) -ptolyl] oxy]-N,N-diethylethylamine,

2- a-cyclohexylidene-a- (p methoxyphenyl) -p-tolyl] oxy]-N,N-dimethylethylamine and the hydrochlorides thereof.

EXAMPLE 4 5- [u-cyclohexylidene-a- (p-methoxyphenyl) -ptolyl] oxy]methyl] -2-0xaz0lid'inethione (A) 3- [a-CYCLOHEXYLIDENE-u.(p-METHOXYPHENYL) p-TOLYL] OXY] -1,2-EPOXYPROPANE To a solution of 4.74g. of a-cyclohexylidene-u-(pmethoxy-phenyl) p cresol (Example 1) in 20ml. of dimethylformamide and 100 ml. of benzene there is added 0.70 g.of 53% sodium hydride in mineral oil. Following 30 minutes stirring atroom temperature there is added 1.60 g. of epichlorohydrin in 20 ml. ofbenzene. The mixture is heated at reflux for 16 hours and thenconcentrated in vacuum. The residue is dissolved in a mixture of waterand ether and then the aqueous and organic phases are separated. Theorganic phase is Washed in turn with water, a saturated solution ofsodium chloride and then taken to dryness. The residue, which is in theform of a gum, is chromatographed on 600 ml. of Florisil (elution with8% acetone in Skellysolve B hexanes) to give 3.44 g. of 3 [[a'.cyclohexylidene-a-(pmethoxyphenyl) p tolyl]oxy] 1,2 epoxypropane as oilycrystals followed :by 1.60 g. of the dimer 1,3-bis[[acyclohexylidene o:(p methoxy-phenyl) p tolyl] oxy]-2-propanol, melting point 157-161 C.After recrystallization from a mixture of methylene chloride andSkellysolve B hexanes, the dimer has a melting point of 157-160 C.

Analysis.-Calcd. for C H O (percent): 80.09; H, 7.70. Found (percent):C, 79.37; H, 7.50.

The oily crystals are rechromatographed on Florisil (elution with 5%acetone in Skellysolve B hexanes). The crystalline fractions arecombined and recrystallized twice from Skellysolve B to yield3-[[a-cyclohexylidene-a-(pmethoxyphenyl) -p-tolyl]oxy]-1,2-epoxypropane.

(B) N-3-[ [a-CYCLOHEXYLIDENE-a- (p-METHOXYPHEN-YL)-p-TOLYL]OXY]-2-HYDROXY-PROPYLSUCCINIMIDE A mixture of 3.92 g. of3-[[a-cyclohexylidene-a-(pmethoxyphenyl)-p-tolyl]oxy]-1,2 epoxypropane(Example 4, step A), 1.18 g. of succinimide and 6 drops of pyridine isheated at reflux for two days. The mixture is chromatographed on 600 ml.of Florisil (elution with a 1:1 mixture of acetone and Skellysolve Bhexanes). The crystalline fractions are combined and recrystallized fromaqueous methanol to yield 2.84 g. ofN-3-[[a-cyclohexylidene-a-(p-methoxyphenyl) ptolyl]oxy1]propylsuccinimide, melting point Ill-121 C. After furtherrecrystallization the product melted at -1315" C.

Analysis.Calcd. for C H NO (percent): C, 72.14; H, 6.95. Found(percent): C, 71.80; H, 6.92.

Using the procedure described in Example 4, step B, but replacing 3 [[acyclohexylidene-a-(p-methoxyphenyl)-p-tolyl] oxy]-1,2-epoxypropane bythe appropriately substituted 3-[[a-cyclohexylidene-a-phenyl-p-tolyl]oxy]-1,2-epoxypropane is productive of the corresponding N 3[Iu-cyclohexylidene-a-phenyl-p-tolyl]oxy]-2-hydroxypropylsuccinimide.Representative of the propyl succinimides so prepared are N-3-{[at-cyclohexylidene-a-(o-methoxyphenyl) -ptolyl]oxy]-,

N-3-[ [a-cyclohexylidene-a-(m-methoxyphenyl) -mtolyl] oxy] N-3[[a-cyclohexylidene-u-phenyl-p-tolyl] oxy] N-3- {a-cyclohexylideneu-(p-tolyl) -p-tolyl] oxy] N-3 la-cyclohexylidene-u- (p-chlorophenyl)-p-tolyl] N-3-[ [a-cyclohexylidene-a- (o-chlorophenyl) -p-to1yl] N-3-[wcyclohexylidene-u- (m-chlorophenyl -p-tolyl]2-hydroxy-propylsuccinimides.

(c) 3 [ta CYCLOHEXYLIDENE a (p METHOXY- PHENYL) p TOLYL] OXY] 2 HYDROXYPROPYL- AMINE HYDROCHLORIDE A mixture of 2.74 g. ofN-3-[[ct-cyclohexylidene-a-(pmethoxyphenyl)-p-tolyl]oxy] 2hydroxy-propylsuccinimide (Example 4, step B) and 11 ml. of 50% sodiumhydroxide in ml. of ethanol is heated at reflux for 16 hours. Themixture is then concentrated at reduced pressure and the residue treatedwith 2.5 N hydrochloric acid. The mixture is extracted with threeportions of methylene chloride. The gum which remains when the extractis taken to dryness is precipitated once from acetone with 2.5 Nhydrochloric acid. There is obtained 2.32 g. of solid 3[[u-cyclohexylidene-a-(p-methoxyphenyl)-ptolyl] oxy]-2-hydroxy-propylamine hydrochloride, which does not show a congruentmelting point.

(D) 3-[ [tr-CY CLOHEXYLIDENE-a- (p-METHOXYPHENYL p-TOLYL] OXY]-2-HYDROXY-PROPYLAMI NE To a solution of 1.30 g. of3-[[ct-cyclohexylidene-a-(pmethoxyphenyl)-p-tolyl] oxy] 2hydroxy-propylamine hydrochloride (Example 4, part C) in 20 ml. ofmethanol there is added 7.3 ml. of 0.49 N methanolic sodium methoxide.The mixture when taken to dryness yields a residue which ispredominantly 3-[[a cyclohexylidene-a-(p-methoxyphenyl) -p-tolyl] oxy]-2-hydroxy-propylamine (E) 5 [[[G CYCLOHEXYLIDENE-a-(p-HETHOXYPHEN- YL)p TOLYLJOXYHVIETHYL] 2 OXAZOLIDINE- THIONE The 3 [[u cyclohexylidene-ot-(p-methoxyphenyl)-ptolyl]oxy]-2-hydroxy-propylamine prepared in Example4, part B is dissolved in 45 ml. of ethanol. There is then added 0.40ml. of carbon disulfide and 1.5 ml. of 25% aqueous sodium hydroxide.Following 4 hours heating at reflux the solution is taken to dryness.The residue is suspended in water, made acidic with 2.5 N hydrochloricacid and the precipitate collected on a filter. Severalrecrystallizations from aqueous acetone affords 0.90 g. of5[[[acyclohexylidene a. (p methoxyphenyl)-p-tolyl]oxy]methyl]-2-oxazolidinethione, melting point -183 C.

Analysis.Calcd. for C t-1 N0 8 (percent): C, 70.38; H, 6.65; N, 3.42; S,7.83. Found (percent): C, 70.07; H, 6.96; N, 3.48; S, 7.43.

9 EXAMPLE 5 a-Cyclopentylidene-a-(p-methoxyphenyl)-p-creiml To anice-cooled solution of the Grignard reagent prepared from 25.7 g. ofp-(Z-tetrahydropyranyloxy)bromobenzene and 2.43 g. magnesium in 250 ml.of tetrahydrofuran there is added 18 g. of cyclopentyl anisyl ketone in200 ml. of tetrahydrofuran. Following 16 hours of standing at roomtemperature, the mixture is cooled in ice and treated with 100 ml. ofsaturated ammonium chloride. Ether is added and the organic phaseseparated from the inorganic phase. The organic phase is washed in turnwith water and a saturated solution of sodium chloride. The waxy solidwhich remains when the solvent is removed is recrystallized twice fromaqueous methanol to give 15.04 g. of acyclopentylidene-u-(p-methoxyphenyl)-p-cresol, melting point 1l2-ll5.5C.

Using the procedure described in Example 5 but re lacing anisylcyclopentyl ketone by phenyl cyclopentyl ketone, p-methylphenylcyclopentyl ketone, and p-chlorophenyl cyclopentyl ketone, there areobtained ot-cyclopentylidenea: phenyl p cresol,a-cyclopentylidene-a-(p-methylphenyl) p cresol anda-cyclopentylidene-a-(p-chlorophenyl)p cresol respectively.

EXAMPLE 6 1-[2-[[a-Cyclopentylidene-a-(p-metlzoxyphenyl)-p-t0Iyl]oxy]ethyl]-pyrrlidine and hydrochloride thereof A solution of 5.60 g. ofa-cycl0pentylidene-a-(p-methoxyphenyl)-p-cresol (Example in 50 ml. ofdimethylformamide and 250 ml. of benzene is treated with 0.85 g. of 56%sodium hydride in mineral oil. When the eirervescence ceases, 5.10 g. ofa 1:1 mixture of B-chloroethylpyrrolidine and toluene is added. Themixture is heated overnight at reflux and the solvent removed in vacuum.The residue is taken up in ether and water. After the organic andaqueous phases are separated, the organic phase is extracted with three50 ml. portions of 2.5 N hydrochloric acid. The extract is then washedwith five 50 ml. portions of methylene chloride. This last solution istaken to dryness and the residue recrystallized twice from a mixture ofmethylene chloride and ethyl acetate. There is obtained 6.50 g. of1[2-[[u-cyclopentylidene-2-(p-methoxyphenyl)-B-tolyl]oxy]ethyl]-pyrrolidinehydrochloride, melting point 196.5-199 C.

Analysis.Calcd. for C H ClNO (percent): C, 72.53; H, 7.79; Cl, 8.57.Found (percent): C, 72.24; H, 7.95; CI, 8.90.

The free base is prepared by basifying the hydrochloride with methanolicsodium methoxide and evaporating the mixture to dryness.

Using the procedure described in Example 6, but replacing acyclopentylidene-(p-methoxyphenyl)-p-cresol by the appropriatelysubstituted tit-cyclopentylidenephenyl-cresol andB-chloroethylpyrrolidine by the appropriately substitutedtertiaryaminoalkyl halide, there are obtained the corresponding[[[a-cyclopentylidene-upheny-tolyl] oxy] alkyl]-tertiaryamines and thehydrochlorides thereof. Representative of the tertiary amines andcorresponding hydrochlorides so prepared are 1- [2-[[a-cyclopentylidene-a- (o-methoxyphenyl) -o-tolyl] oxyl] ethyl] L [2-[u-cyclopentylidene-w (o-methoxyphenyl) -m-tolyl] oxy] ethyl] l- [2-[a-cyclopentylideneu-phenyLp-tolyl] oxy] ethyl] 1- [2-[a-cyclopentylideneup-methylphenyl) -p-tolyl] 1- [2-[[ot-cyclopentylidene-a- (pchlorophenyl) -p-tolyl] oxy] ethyl] 1- [2-[ix-cyclopentylideneoco-chlorophenyl p-tolyl] yl y r,

1- [2- [a-cyclopentylidene-ot- (m-chlorophenyl) -p-tolyl] 1- [2-[[a-cyclopentylidene- (p-methoxyphenyl -o-tolyl] 1- 2-[[a-cyclopentylidene-u- (m-methoxyphenyl) -mtolyl] oxy] ethyl] 1- [2-[a-cyclopentylidene-a- (m-methoxyphenyl-p-tolyl] oxy] ethyl] 1- [3-[a-cyclopentylidene-a- (m-methoxyphenyl) -p-tolyl] 1- [4-[u-cyclopentylidene-a- (p-methoxyphenyl) p-tolyl] oxy] butyl]pyrrolidine, v

l- [2- [oL-cyclopentylidene-ap-methoxyphenyl) -p-tolyl] oxy] ethyl]piperazine,

1- [2 [u-cyclopentylidene-2- p-methoxyphenyl) -p-tolyl] oxy] ethyl]piperazine,

4- [2- [a-cyclopentylidene-a- (p-methoxyphenyl) -ptolyl] oxy] ethyl]morpholine,

1 [2- u-cyclop entylidene-u- (p-methoxyphenyl p-tolyl] oxy] ethyl]hexamethyleneimine,

1- [2- [a-cyclop entylidene-ap-methoxyphenyl) -p-tolyl] oxy] ethyl] -3-methylpyrrolidine,

1- 2- [u-cyclopentylidene-a- (p-methoxyphenyl) -p-tolyl oxy] ethyl]-2-methylpiperidine,

1- 2- [u-cyclopentylidene-ap-methoxyphenyD -p-tolyl] oxy] ethyl]-2-methylpiperidine,

2- [u-cyclop entylidene-ap-methoxyphenyl) -p-tolyl] oxy] ethyl]-N,N-diethylethylamine,

2- [a-cyclopentylideneoc- (p-methoxyphenyl -p-tolyl] oxy] ethyl]-N,N-dimethylethylamine, and the hyld rochlorides thereof.

' EXAMPLE 7 A solution of 5.60 g. ofot-cyclopentylidene-a-(p-methoxyphenyl)-p-cresol (Example 5) in ml. ofmethanol is treated with 5 ml. of 4.46 N sodium methoxide in methanol.Following 15 minutes stirring at a temperature of 25 C. 2.50 g. of1-chloro-2,3-propanediol is added and the mixture heated at reflux for16 hours. The methanol is removed and the residue dissolved in a mixtureof ether and Water. After the organic phase is separated from theaqueous phase, it is washed with water, a saturated solution of sodiumchloride and then taken to dryness. The residual gum is chromatographedover Florisil (elution with 10 and then 50% acetone in Skellysolve Bhexanes) to give 3.69 g. of the crude product. This product isrecrystallized twice from aqueous methanol to afford 3.50 g. of3-[[a-cyclopentylidene-a- (p methoxyphenyl)-p-tolyl]oxy]-1,2,-propanediol, melting point 56-68" C.

Analysis.Calcd. for C H O /2H O (percent): C, 72.69; H, 7.49. Found(percent): C, 73.38; H, 7.63.

Using the procedure described in Example 7, but replacing orcyclopentylidene oz (p-methoxyphenyD-pcresol by the appropriatelysubstituted (at-cyclopentylideneu-phenyl-cresol is productive of thecorresponding [[0:- cyclohexylidene a phenyl-tolyl]oxy]-1,2-propanediol.Representative of the propanediols so obtained are 3-[[u-cyclopentylidene-a- (o-methoxyphenyl) -o-tolyl] oxy] 3 [et-cyclopentylidene-u- (m-methoxyphenyl -m-tolyl] 3-[[a-cyclopentylidene-u-phenyl-p-tolyl] oxy] 3- [u-cyclopentylidene-u-(p-methylphenyl) -p-tolyl] 1 1 Similarly, using the procedure describedin Example 7, but replacing 1-chloro-2,3-propanediol with 1-chloro-3,4-butanediol there is obtained4-[a-cyclopeutylidene-a-(pmethoxyphenyl)p-tolyl]-l,2-butanediol.

EXAMPLE 8 5 [a-cyclopentylidene-a- (p-methoxyphenyl) -p-tolyloxyjmethyl]-2-oxaz0lidinethione A) a [[a CYCLOPENTYLIDENE a (p METHOXY-PHENYL) p TOLYLJOXY] 1,2 EPOXYPROPANE To a solution of 10.00 g. ofa-cyclopentylidene-a-(pmethoxyphenyl) p cresol (Example 5) in 50 ml. ofdimethylformamide and 250 ml. of benzene there is added 1.55 g. of 56%sodium hydride in mineral oil. Following 30 minutes stirring at roomtemperature there is added 3.36 g. of epichlorohydrin in ml. of benzene.The mixture is heated at reflux for 16 hours and then concentrated invacuum. The residue is dissolved in a mixture of water and ether andthen the organic phase separated from the aqueous phase. The organicphase is washed in turn with water, a saturated solution of sodiumchloride and then taken to dryness. The residue is chromatographed onFlorisil (elution with a mixture of acetone and Skellysolve B hexanes).Those fractions which are similar by thin layer chromatography arecombined to afford 5.40 g. of 3-[[a-cyclopentylidene-u-(pmethoxyphenyl)p-tolyl]oxy]-1,2-epoxypropane, which is in the form of a gum.

(B) N 3 [[a CYCLOPENTYLIDENE a (p METHOX- YPHENYL) p TOLYL10XY] 2HYDROXY PRO- PYLSUCCINIMIDE A mixture of 5.10 g. of3-[[a-cyclopentylidene-a-(pmethoxyphenyl)-ptolyl]oxy]-1,2-epoxypropane,1.60 g. of succinimide and 7 drops of pyridine is heated at reflux fortwo days. The mixture is chromatographed on 600 ml. of Florisil (elutionwith a 1 :1 mixture of acetone and Skellysolve B hexanes). The fractionswhich show similar compositions on a thin layer chromatograph arecombined to yield 3.72 g. ofN-3-[{u-cyclopentylidene-a-(p-methoxyphenyl)-p-tolyl]oxy]Z-hydroxy-propylsuccinimide in the form of a gum.

Using the procedure described in Example 8, part B, but replacing3-[[a-cyclopentylidene-a-(p-methoxypheny1)-p-to1yl]-oxy]-l,2-epoxypropaneby the appropriately substituted 3E[a-cyclopentylidene-a-phenyl-tolyl]oxy]- 1,2-epoxypropane is productiveof the corresponding N-3- [[a-cyclopentylidene-e-phenyl-tolyl]oxy] 2hydroxypropylsuccinimide. Representative of the succinimides so obtainedare N-3-[ [a-cyclopentylidene-a- (o-methoxyphenyl) -p-tolyl] N-3-[[a-cyclopentylidene-a-(m-methoxyphenyl)-m-tolyl] N-3-[[a-cyclopentylidene-m-phenyl-p-tolyl] oxy] N-3-[[m-cyclopentylidene-a-(methylphenyl) -p-tolyl] N-3-{[a-cyclopentylidene-a- (p-chlorophenyl) -p-to1yl] N-3-[a-cyclopentylidene-a- (o-chlorophenyl-p-tolyl] N-3 [m-cyclopentylidene-a- (m-chlorophenyl) -p-tolyl] oxy]-2-hydroxy-propylsuccinimide.

(c) 3 [[a. CYCLOPENTYLIDENE a (p METHOXY- PHENYL) p TOLYL]OXY] 2 HYDROXYPROPYL- AMINE HYDROIODIDE \A mixture of 0.94 g. ofN-3-[[et-cyclopentylidene-ot-(p-methoxyphenyl)-p-tolyl]oxy]-2-hydroxy-propylsuccinimide (Example 8,part B) and 3 ml. of 50% sodium hydroxide in 30 ml. of ethanol is heatedat reflux for 16 hours. The mixture is then concentrated at reducedpressure and the residue treated with 2.5 N hydroiodic acid. The mixtureis extracted with three portions of methylene chloride. The residuewhich remained when the gum is 12 taken to dryness is precipitated oncefrom acetone with 2.5 N hydroiodic acid and then recrystallized twicefrom a mixture of benzene and cyclohexane. There is obtained3-[Ea-cyclopentylidene oz (p-methoxyphenyl)-p-tolyl]oxy]-Z-hydroxypropylamine hydroiodide, melting point 144-147 C.

Analyses.Calcd. for C H lNO (percent): C, 54.89; H, 5.86. Found(percent): C, 54.53; H, 5.95.

Using the procedure described in Example 8, part C, but replacing N 3[[u-cyclopentylidene-a-(p-methoxyphenyl)-B-tolyl]oxy]-2-hydroxy-propylsuccinimideby N- 3-[ [ot-cyclopentylidene a; phenyl-p-tolylloxy] 2hydroxy-propylsuccinimide,N-3-[[oz-cyclopentylidene-a-(prnethoxyphenyl)-p-tolyl]oxy] 2hydroxypropylsuccinimide and N-3-[[e-cyclopentylidenea-(p-chlorophenyl)-p-tolyl]oxy]-2-hydroxy-propylsuccinimide, there are obtained 3-[ot-cyclopentylideneu-phenyl] -p-tolyl] oxy] -2-hydroxypropylamiuehydroiodide,

3-[ [a-cyclopentylidene-a-(p-methylphenyl) -p-tolyl]oxy]Z-hydroxypropylamine hydroiodide, and

3-[ [a-cyclopentylidene-a-(p-chlorophenyl)-p-tolyl]oxy]Z-hydroxypropylamine hydroiodide respectively.

(D) '3 [[a CYCLOPENTYLIDENE a. (p METHOXY- PHENYL) p TOLYLJOXY] 2HYDROXY PROPYL- AMINE To a solution of 1.50 g. of3-[[u-cyclopentylidene-2- (p-methoxyphenyl)-p-toly1]oxy]Z-hydroxypropylamine hydroiodide (Example 8, part C) in 20 ml. ofmethanol there is added 6.4 m1. of 0.49 N methanolic sodium methoxide.The mixture when taken to dryness yields a residue which ispredominantly 3-[[u-cyclopentylidene-a-(pmethoxyphenyl)-p-tolyl]oxy]-2-hydroxy-propylamine.

(E) 5 [[[41 CYCLOPENTYLIDENE a. (p METHOXY- PHENYL) p TOLYLIIOXY] 2OXAZOLIDINETHI- ONE To a solution of 1.68 g. of3-[[u-cyclopentylidene-a- (p-methoxyphenyl)-p-tolyl]oxy]2-hydroxy-propylamine (Example 8, part D) in 70 ml. of ethanol there isadded 0.62 ml. of carbon disulfide and 2.7 m1. of 25 potassiumhydroxide. The mixture is heated for four hours at reflux and then takento dryness. The residue is suspended in water and made acidic with 2.5 Nhydrochloric acid. Then the precipitate is collected and chromatographedon ml. of magnesium silicate (elution with 25% acetone in Skellysolve Bhexanes). .The crystalline fractions are combined and recrystallizedfrom aqueous acetone to give 0.54 g. of crystalline 5-[[ct-cyclopentylidene-a-(p-methoxyphenyl)-ptolyl] oxyJmethyl]2-oxazolidenethione, melting point 1545-1565 C.

Analysis.-Calcd. for C H N0 S '(percent): C, 69.84; H, 6.37; S, 8.11.Found (percent): C, 69.74; H, 6.16; S, 8.3 1.

Using the procedure of Example 8, part B, but replacing 3[[a-cyclopentylidene cc (p-methoxyphenyl)-p-tolyl] oxy]-2-hydroxy-propylamine by 3 [[oc cyclopentylidenea-phenyl-p-tolynoxy] 2hydroxy-propylamine,3-[[mcyclopentylidene-u-(p-methylphenyl)-p-tolyl]oxy]2-hydroxy-propylamine, and 3[[ot-cyclopentylidene-u-(pchlorophenyl)-p-tolyl] oxy]-2-hydroxy-propylamine, there are obtained 5I[[a-cyclopentylidene-a-phenyl-p-tolyl] oxy] methyl] 2oxazolidinethione, 5[[[a-cyclopentylidene-a-(p-methylphenyl)-p-tolyl]oxy]methyl]2-oxazolidinethione and 5-[[a-cyclopentylidene-u-(p-chloropheny1)-p-tolyl]oxy]methyl} 2oxazolidenethione respectively.

I claim:

1. A compound having the formula wherein m is an integer from one to 4,and R and R individually are similar or different alkyl groupscontaining from one to 4 carbon atoms, inclusive; and when takentogether with the attached nitrogen atom form a pyrrolidino,methylpyrrolidino, piperazino, methylpiperazino, piperidino,methylpiperidino, morpholino, hexamethylenimino, or homopiperazinogroup.

2. A compound of claim 1 wherein methylpyrrolidino isZ-methylpyrrolidino, 2,2 dimethylpyrrolidino, or 3- methylpyrrolidino.

3. A compound of claim 1 wherein methylpyrrolidino isZ-methylpyrrolidino, 2,2-dimethylpyrro1idino, or 3-rnethylpyrrolidino.

4. A compound of claim 1 wherein methylpiperidino 14 isZ-methylpiperidino, 3-methylpiperidino, or 4,4-dimethylpiperidino.

5. A compound of claim 1 wherein n is 4 or 5, and R is alkoxy containingfrom one to 4 carbon atoms, inclusive.

6. A compound of claim 5 wherein n is 4, R is p-methoxy, and OR isp-pyrrolidinoethyloxy.

7. A compound of claim 5 wherein n is 5, R is p-methoxy, and OR isp-pyrrolidinoethyloxy.

References Cited UNITED STATES PATENTS 3,288,806 11/1966 De Wald260326.5 3,320,271 5/1967 Lednicer 260-3265 X ALEX MAZEL, PrimaryExaminer J. A. NARCAVAGE, Assistant Examiner US. Cl. X.R.

260--239 B, 239 BC, 268 R, 293.83, 295.55, 307 C, 326.5 FM, 343.7, 348R, 570 R, 618 R; 424244, 248, 250, 267, 274, 278, 320, 340

' case 2462 UNITED STATES PATENT ()FFICE (CERTIFICATE OF CORREUNQNPatent No. 3 5 42 Dated P Fl l 5, 97

Inventoflg) Dan 1e l Ledn l ce It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

Column 6, line 62, for "[[[cyclohexyldlene read [cyclohexy l idene-Column 6, l i ne 70, for 1-2- read 1 [2- Column 7, l ine 9, for "l-2-read l [2- Column 7, l lne 12, for oxylethyl 1-" read o y 1p ropylColumn 7, l i r.e 15, for 1- [21 read 1- [2- Column 10,

l i ne 8, for lethyl 1-" read lpropyl 1-1 Column 13, l i nes 20-22, c laim 3, For "3. A compound 0F claim 1 wherein me thylpyrrol i dl no i s2-methYlpyrrol i di no, 2,2-dlmethy lpyrrol i dlno, or

3-methy l py rrol idi no." read 5 A compound of cla i m l ,7 where i nmethy l pi pe raz i no i s 2-me thy l pi pe raz i no, l-rnethy lpl peraz i no, or

'Zfll-dimethylpiperazinm Signed and sealed this 27th day of March 1973.

(SEAL) Attest:

EDWARD l-I.PLETCHER,JR. ROBERT GOTTSCHALK Attesting Officer Commissionerof Patents USCOMM-DC 60376 3 59 U 5. GOVERNMENI PRINTING CFHCE I 95?0-36 -35

